This is a proposal to continue an ongoing and productive clinical research project using drug discrimination procedures in human volunteers to characterize the discriminative stimulus characteristics, the subjective, behavioral, and physiological effects, and the profile of opioid receptor activity of various opioids. Attention is directed especially to the opioid mixed agonist-antagonists. These studies are conducted in a well- control led and supervised residential laboratory where the effects of the drugs can be carefully assessed, and where volunteers remain stable and well cared for. In the drug discrimination procedure, volunteers are trained to recognize specific reference drugs and then are tested with novel drugs or doses to assess their similarity to these known standards. Behavioral discrimination data are collected concurrently with subjective effects data, physiological data, and psychomotor/cognitive performance data. The studies provide important data about the opioid receptor mechanisms through which the various opioids produce their effects, about the cross-species generality to humans of the extensive drug discrimination data from preclinical laboratory research, about the relationship between subjective and discriminative drug effects, and about the influence and application of procedural variations in the behavioral drug discrimination procedure itself. Twelve studies are proposed. Three studies will investigate the effect of mu-receptor antagonism with naltrexone on the effects of pentazocine, nalbuphine, and butorphanol. Three studies will investigate the effect of kappa-receptor antagonism with buprenorphine on the effects of pentazocine, nalbuphine, and butorphanol. Other studies will investigate: (1) adaptation of the drug discrimination procedure to characterize the time course of alternative dosage forms of fentanyl and of morphine; (2) the utility of a within- session dose-effect assessment procedure for enhancing the speed and efficiency of human drug discrimination research; (3) the effect of opioid tolerance on response to hydromorphone and butorphanol; (4) the stimulus similarity of mixed agonist-antagonists to sedative drugs; (5) the comparative response of males versus females to opioids; and, (6) whether drug use and community functioning change following clinical pharmacology research participation.
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